The goal of the proposed research is to use mesoporous silica nanoparticles with bistable molecular machines to deliver anticancer drugs. The active structures are nanomachines that consist of a solid silica support that contains designed pores, and moving parts that trap drug molecules and release them from the pores only on external command or under desired conditions. Two types of machines, nanoimpellers that actively eject molecules from the pores, and nanovalves that block and unblock the entrances to the pores will be used to control the delivery of drugs. The assembly is coated with molecules or proteins that target the capsules to cancer cells. The first specific aim is to improve and optimize nanomachines (a pH activated valve, a light-activated impeller, a light activated valve) that were developed in the principal investigators laboratories, modify the surfaces for specific cancer cell targeting, and optimize their performance. The second aim will demonstrate operation of the machines in human cancer cells by studying the release of a fluorescent DNA binding agent and to demonstrate the delivery and on-demand release of anticancer drugs (paclitaxel, camptothecin and doxorubicin) in human carcinoma cell lines. Finally, the third aim will evaluate and utilize the nanoparticles in human tumor xenografts grown in athymic mice. By having the valves open only in a tumor, it will be possible to achieve release of anticancer drugs only at specific sites or in response to specific stimuli, thus eliminating unwanted effects on non-cancerous cells. The nano valves and impellers allow sophisticated control of the delivery of the drugs.